Abstract
Increased circulating levels of apolipoprotein C3 (APOC3) predict cardiovascular disease (CVD) risk in humans, and APOC3 promotes atherosclerosis in mouse models. APOC3's mechanism of action is due in large part to its ability to slow the clearance of triglyceride-rich lipoproteins (TRLs) and their remnants when APOC3 is carried by these lipoproteins. However, different pools and forms of APOC3 exert distinct biological effects or associations with atherogenic processes. Thus, lipid-free APOC3 induces inflammasome activation in monocytes whereas lipid particle-bound APOC3 does not. APOC3-enriched LDL binds better to the vascular glycosaminoglycan biglycan than does LDL depleted of APOC3. Patterns of APOC3 glycoforms predict CVD risk differently. The function of APOC3 bound to HDL is largely unknown. There is still much to learn about the mechanisms of action of different forms and pools of APOC3 in atherosclerosis and CVD, and whether APOC3 inhibition would prevent CVD risk in patients on LDL-cholesterol lowering medications.